EP1631298B1 - Glycosaminoglykane zur behandlung emotionaler störungen - Google Patents

Glycosaminoglykane zur behandlung emotionaler störungen Download PDF

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Publication number
EP1631298B1
EP1631298B1 EP04741606A EP04741606A EP1631298B1 EP 1631298 B1 EP1631298 B1 EP 1631298B1 EP 04741606 A EP04741606 A EP 04741606A EP 04741606 A EP04741606 A EP 04741606A EP 1631298 B1 EP1631298 B1 EP 1631298B1
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European Patent Office
Prior art keywords
animals
day
test
animal
glycosaminoglycans
Prior art date
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Expired - Lifetime
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EP04741606A
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English (en)
French (fr)
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EP1631298B8 (de
EP1631298A1 (de
Inventor
Umberto Cornelli
Luigi De Ambrosi
Stanley Lorens
Jawed Fareed
John Lee
Israel Hanin
Ronald Mervis
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Priority to SI200430547T priority Critical patent/SI1631298T1/sl
Priority to PL04741606T priority patent/PL1631298T3/pl
Publication of EP1631298A1 publication Critical patent/EP1631298A1/de
Publication of EP1631298B1 publication Critical patent/EP1631298B1/de
Priority to CY20071101592T priority patent/CY1107092T1/el
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention relates to novel pharmacological applications of glycosaminoglycans, in particular those having an average molecular weight of 2400 ( ⁇ 200) D.
  • Emotional disturbances belong to the area of psychiatric illnesses included in depressive, anxiety, psychotic and manic syndromes and are mainly expressed in the form of an abnormal reaction to the surroundings, ranging from aggressiveness, to a state of confusion and to apathy.
  • Emotional disturbances are treated pharmacologically in various ways depending on their origin.
  • Unipolar affective disorders are treated with tricyclic antidepressants such as imipramine or heterocyclic antidepressants such as selective serotonin uptake inhibitors like fluoxetine, or with monoamine-oxidase inhibitors such as phenelzine (drugs of this type are preferably included in the pharmacology textbook "The pharmacological basis of therapeutics", Chapter 19, X edition 2001).
  • bipolar affective disorders are treated with lithium, valproic acid or other drugs with anticonvulsant action (drugs of this type are preferably included in Chapter 20 of the aforementioned pharmacology textbook).
  • Primary anxiety disorders such as generalized anxiety syndromes and obsessive-compulsive syndromes, are treated with the categories of products already mentioned or with benzodiazepines and/or buspirone.
  • Pharmacological treatment of emotional disturbances is, however, accompanied by a number of side effects including, among others, alteration of the normal state of consciousness.
  • ECM extracellular matrix
  • glycosaminoglycans have a hyperanxiogenic effect when injected intracerebrally.
  • Benzodiazepine and amitriptyline and antisclerotic agents were used in the treatment of elderly patients with depressive syndromes and senile dementia.
  • EP1181024 discloses the use of glycosamingolycans having an average molecular weight equal to 2400 ⁇ 200 for the preparation of pharmaceutical compositions suitable for the treatment of Alzheimer's disease or SDAT (Senile Dementia of Alzheimer's Type) and of the cerebral neurological lesions from ictus and traumas.
  • glycosaminoglycans selected from heparin and heparan sulphate with an average molecular weight of 2400 ( ⁇ 200) D are able to correct emotional dysfunctions selected from the group consisting of : depressive disorders, anxiety disorders, anxiety neurosis, agitation and confusion without altering the normal state of consciousness, because of their ability to prevent or reduce the alteration of the extracellular matrix (ECM) in the brain.
  • ECM extracellular matrix
  • fraction of the above cited glycosaminoglycans having an average molecular weight of 2400 ( ⁇ 200) D can be used for the preparation of pharmaceutical compositions suitable for the treatment of the aforementioned emotional dysfunctions.
  • the present invention therefore relates to the use of a fraction of glycosaminoglycans with an average molecular weight of 2400 ( ⁇ 200) D for the preparation of pharmaceutical compositions capable of preventing or reducing pathologic changes of the extracellular matrix in the brain.
  • Said composition can therefore be used in the treatment of emotional dysfunctions and in particular in depressive disorders, anxiety disorders, anxiety neurosis, agitation and confusion.
  • glycosaminoglycans are the most abundant heteropolysaccharides in the human body and are made up of repeating units of disaccharides that are formed in their turn from one or two modified sugars N-acetylgalactosamine or N-acetylglucosamine and from a uronic acid, for example glucuronate or iduronate.
  • the present invention relates in particular to glycosaminoglycan fractions with an average molecular weight of 2400 ( ⁇ 200) D.
  • the GAGs of the present invention are obtained from hyaluronates, dermatan sulphates, chondroitin sulphates, heparin and heparan sulphates, or keratan sulphates.
  • the said fractions can be produced by depolymerization of the corresponding glycosaminaglycan(s) in various steps comprising: irradiation of the glycosaminflglycan(s) with gamma radiation, followed by gel filtration and ultrafiltration.
  • Methods for obtaining the glycosaminoglycans according to the present invention are known in the art.
  • the fractions of GAGs of the present invention are obtained from heparin, for example according to the method described in EP 1181024 .
  • BN rats Thirteen Brown Norway (BN) rats were used, obtained from Harlan Sprague-Dawley Inc. (Indianapolis In.) with weight of 300-350 g and age of 11 months.
  • the animals were adapted to the new environment for two weeks before beginning any treatment or biological test. Assignment to treatment with the drug (7 animals) or with the vehicle alone (6 animals) was randomized. The animals were kept in individual cages and were assessed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) in an environment with controlled temperature (22-26°C) and with circadian light rhythms of 12 h (light starting from 7:00 hours). The animals were given food and water ad libitum. All assessments of behaviour were carried out in a sound-proofed environment next to the living quarters and between the hours of 09:00 and 13:00. At the end of the experiment, i.e.
  • AALAC Laboratory Animal Care
  • a glycosaminoglycan fraction with average molecular weight of 2400 ( ⁇ 200) D (identified hereinafter with the symbol C3) was obtained by depolymerization of heparin by gamma-irradiation and successive fractionation to obtain the desired molecular weight, as described in EP 1118024 , and consisted of a water-soluble white powder. This was dissolved in drinking water at a concentration such that the animals received a daily administration of 25 mg/kg for a period varying between 42 to 44 days. The water consumption of the individual animals was measured during the first two weeks of adaptation. During the experiment, the drinking water containing C3 was renewed every 3-4 days.
  • Week Procedure 1 Arrival of the animals and adaptation in individual cages 2 Start of measurement of the amount of water consumed 3 Start of administration of C3 (25 mg/kg) or of vehicle 5 Open-field (OF) test - 12 minutes 6-7 Morris water maze (MWM) Acquisition (6 days) Reversal (3 days) 8 Context-dependent fear conditioning (CDFC) Adaptation (2 days) Conditioning (3 days) 9 Sacrifice of the animals
  • the behaviour resulting from exposure to a new environment permits measurement of a neophobic response (fear of new environments) and of the exploratory response.
  • the OF test was carried out on a platform with the dimensions 100 cm x 100 cm x 40 cm high.
  • the walls were constructed of varnished plywood.
  • the floor was painted white and divided into 25 squares (25 cm x 25 cm) marked out with a thin black line. In the corners located at the edges of the square formed by the nine central squares of the platform there were four holes 3.5 cm in diameter.
  • the platform was located in a sound-proofed room with indirect lighting.
  • the animals were placed at the centre of the platform and were observed for 12 minutes.
  • the OF was washed with a 70% ethanol solution to remove any olfactory stimulus associated with the individual animal.
  • Learning and spatial memory can be evaluated using the water maze, in which the animal's ability to learn and remember the location of a platform that permits it to get out of the water is measured.
  • the test can evaluate the state of excitation or sedation of the animals.
  • the maze was constructed from a plastic cylinder (152 cm in diameter and 74 cm high) painted white, filled with water to a height of 56 cm and divisible into quadrants. Half-way between the centre and the edge, 1.5 [cm] below the surface of the water, there was a 9 cm 2 platform. The water was made opaque by adding milk powder and its temperature was maintained in the range 22-26°C. The reference points outside the maze were kept constant. The behaviour of each animal was recorded on video (SMART Video Tracking System, San Diego Instruments, San Diego, CA). The video camera connected to the computer was situated above the centre of the maze. The computer calculated: 1) the length of the path (cm) taken by the animal to reach the hidden platform; 2) the pause (sec) and the distance (cm) travelled in each quadrant; 3) the latency (sec) for finding and climbing onto the platform.
  • the animals were submitted to the test 4 times a day. In each test the animals were placed at the edge of the maze. The platform was always located in the same place (quadrant 1) for the first 6 days (learning) and was then put in a different position (quadrant 3) for the "reversal" test carried out on the next three days 7-9.
  • the animals were put in quadrant 2, next to the one containing the platform, i.e. quadrant 1.
  • the animals were placed in the adjacent quadrants moving clockwise. The test lasted until the animal reached the platform or up to a maximum of 60 seconds. If the animal did not succeed in reaching the platform in 60 seconds it was gently placed on the platform and left undisturbed for 60 seconds. Each animal was left on the platform for 60 seconds and repeated the test immediately afterwards. At the end of the four tests the animal was gently dried with a towel and put back in its cage.
  • CDFC text-dependent fear conditioning
  • This test measures an animal's ability to learn and remember a conditioned stimulus (CS) paired to an adverse unconditional stimulus (UCS).
  • CS conditioned stimulus
  • UCS adverse unconditional stimulus
  • the test permits analysis of the animal's ability to learn and remember the relation between events (“foreground”) that are conditioned (CS or light) and unconditional (UCS mild electric shock) and the environment (“background”).
  • the animals were adapted to a first environmental context (context A) for two consecutive days.
  • Contexts A and B were represented by small chambers (48 cm long x 25 cm deep x 28 cm high). The experiment lasted 8 minutes.
  • the floor consisted of a grating formed from metal tubes with diameter of 2.5 mm, 10 mm apart (centre-to-centre).
  • the walls of the chamber were all of Plexiglas TM , the front wall was transparent, that at the rear was black, and the others were white.
  • the 7.5 W lamp for the light stimulus was at the centre of one of the side walls of the chamber, positioned 14 cm from the rear of the chamber.
  • the "foreground" conditioning of the third day was as follows. After an interval of 2 minutes, the light was switched on (CS) and 20 seconds later an electric shock was applied to the animal's feet ("foot shock"), via the metal grating, lasting 2 seconds with a strength of 0.8 mA of alternating current, supplied from a Grason-Stadler generator, model E1064GS. The animals were submitted to another two sessions of CS and UCS each with an interval of 2 minutes, giving a total of 3 paired CS-UCS. All the sessions were video recorded and evaluated later.
  • context B On the fifth day, context B was used. The chamber dimensions were identical to those in context A. However, the grating and the rear wall were replaced with a plywood panel. The chamber was cleaned using PetZyme TM (which removes colour and odour) immediately after each session. The PetZyme TM causes olfactory stimuli different from those of the 70% ethanol solution used in context A on days 1 to 5. After an interval of two minutes the CS was applied (light for 20 sec) three times with 2-minute intervals. No UCS was applied. Therefore the fifth day served for measuring the foreground conditioning, i.e. the association between environment and hostility. Freezing was measured as on the third day.
  • the amount of fluid consumed daily by the animals was 35.7 ⁇ 1.1 ml and the C3 had no effect on this consumption.
  • Freezing time (seconds): mean ⁇ SE in the sessions on day 5 Session Freezing time C3 Controls 1 18 ⁇ 6.2 12 ⁇ 4.0 2 90 ⁇ 4.0 74 ⁇ 5.3 3 110 ⁇ 4.5 80 ⁇ 12.0 * 4 110 ⁇ 4.2 106 ⁇ 6.2 * U test: p ⁇ 0.05
  • the glycosaminoglycans with an average molecular weight of 2400 (V200) D can therefore be used for the preparation of pharmaceutical compositions that are suitable for the treatment of emotional dysfunctions.
  • compositions include a pharmaceutically effective quantity of the active principle together with pharmaceutically acceptable diluents or excipients and can be in forms that are suitable for subcutaneous, intramuscular, intravenous and oral administration.
  • Examples of pharmaceutically acceptable diluents or excipients are, for example: physiological saline solution, colloidal silica.
  • compositions normally contain a quantity of glycosaminoglycans in the range from 10 mg to 100 mg.
  • Treatment of emotional dysfunctions comprises administration of approx. 10 mg to 400 mg/day of active principle to the patient.
  • administration of 10-50 mg/day is preferred for subcutaneous, intramuscular and intravenous administration, whereas administration of 50-100 mg/day is preferred in the case of oral administration.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (3)

  1. Verwendung einer Glukosaminoglykan-Fraktion mit einem mittleren Molekulargewicht von 2400 (± 200) D, die durch Depolymerisierung eines Glukosaminoglykans, ausgewählt aus der Gruppe bestehend aus Heparin und Heparansulfat, für die Herstellung von pharmazeutischen Zusammensetzungen erhalten wurde für die Behandlung von emotionalen Dysfunktionen, ausgewählt aus der Gruppe bestehend aus depressiven Störungen, Angst-Störungen, Angstneurose, Agitation, Konfusion.
  2. Verwendung gemäß Anspruch 1, wobei genannte Glukosaminoglykan-Fraktion durch Depolymerisierung von Heparin erhalten wird.
  3. Verwendung gemäß den Ansprüchen 1-2, wobei genannte pharmazeutische Zusammensetzungen von 10 bis 100 mg von der genannten Glukosaminoglykan-Fraktion mit einem mittleren Molekulargewicht von 2400 (± 200) D enthalten.
EP04741606A 2003-05-21 2004-05-19 Glycosaminoglykane zur behandlung emotionaler störungen Expired - Lifetime EP1631298B8 (de)

Priority Applications (3)

Application Number Priority Date Filing Date Title
SI200430547T SI1631298T1 (sl) 2003-05-21 2004-05-19 Glikozaminglikani za zdravljenje emocionalnih disfunkcij
PL04741606T PL1631298T3 (pl) 2003-05-21 2004-05-19 Glikozaminoglikany do leczenia zaburzeń emocjonalnych
CY20071101592T CY1107092T1 (el) 2003-05-21 2007-12-14 Χρηση γλυκοζαμινογλυκανων για τη θεραπεια συναισθηματικων δυσλειτουργιων

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT001023A ITMI20031023A1 (it) 2003-05-21 2003-05-21 Glicosaminoglicani aventi peso molecolare medio 2400 d atti al trattamento delle disfunzioni emozionali.
PCT/EP2004/050860 WO2004103381A1 (en) 2003-05-21 2004-05-19 Glycosaminoglycans for treatment emotional dysfunctions

Publications (3)

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EP1631298A1 EP1631298A1 (de) 2006-03-08
EP1631298B1 true EP1631298B1 (de) 2007-09-19
EP1631298B8 EP1631298B8 (de) 2008-12-24

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EP04741606A Expired - Lifetime EP1631298B8 (de) 2003-05-21 2004-05-19 Glycosaminoglykane zur behandlung emotionaler störungen

Country Status (20)

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US (1) US7812005B2 (de)
EP (1) EP1631298B8 (de)
JP (1) JP4757197B2 (de)
KR (1) KR20060025142A (de)
CN (1) CN100377717C (de)
AT (1) ATE373480T1 (de)
AU (1) AU2004241748B2 (de)
CA (1) CA2526201A1 (de)
DE (1) DE602004009068T2 (de)
DK (1) DK1631298T3 (de)
ES (1) ES2294507T3 (de)
IL (1) IL171981A (de)
IT (1) ITMI20031023A1 (de)
NO (1) NO20056089L (de)
NZ (1) NZ544238A (de)
PL (1) PL1631298T3 (de)
PT (1) PT1631298E (de)
RU (1) RU2353371C2 (de)
WO (1) WO2004103381A1 (de)
ZA (1) ZA200510132B (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101584704B (zh) * 2008-05-23 2010-12-15 鲁南制药集团股份有限公司 肝素、低分子肝素可药用盐或其衍生物的医药用途
CN107760713B (zh) * 2016-08-23 2020-05-05 中国科学院上海药物研究所 一种非人哺乳动物神经精神疾病动物模型的建立方法及其用途
CN112438991B (zh) * 2019-08-29 2024-03-15 鲁南制药集团股份有限公司 肝素、或其衍生物、或其可药用盐的医药用途

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4351938A (en) * 1980-05-19 1982-09-28 Riker Laboratories, Inc. Anticoagulant substance
US4916219A (en) * 1985-03-28 1990-04-10 University Of Iowa Research Foundation Oligosaccharide heparin fragments as inhibitors of complement cascade
IT1205042B (it) * 1987-05-28 1989-03-10 Crinos Industria Farmaco Composizione farmaceutica ad attivita' terapeutica per il trattamento della demenza senile di tipo alzheimer
US5605938A (en) 1991-05-31 1997-02-25 Gliatech, Inc. Methods and compositions for inhibition of cell invasion and fibrosis using dextran sulfate
FR2763848B1 (fr) * 1997-05-28 2000-01-28 Rhone Poulenc Rorer Sa Utilisation des heparines de bas poids moleculaire pour la prevention et le traitement du trauma du systeme nerveux central
FR2763849B1 (fr) * 1997-05-28 2000-09-15 Rhone Poulenc Rorer Sa Utilisation des heparines de bas poids moleculaire pour la prevention et le traitement des oedemes cerebraux
JP4412756B2 (ja) * 1998-02-26 2010-02-10 生化学工業株式会社 新規多糖誘導体、その製造法及びそれを有効成分とする医薬組成物
IT1312107B1 (it) 1999-05-14 2002-04-04 Umberto Cornelli Glicosaminoglicani aventi peso molecolare medio di 2400 d atti altrattamento della demenza senile

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Publication number Publication date
IL171981A0 (en) 2006-04-10
ITMI20031023A0 (it) 2003-05-21
DK1631298T3 (da) 2008-01-28
KR20060025142A (ko) 2006-03-20
US7812005B2 (en) 2010-10-12
PT1631298E (pt) 2007-12-31
DE602004009068T2 (de) 2008-06-19
EP1631298B8 (de) 2008-12-24
NZ544238A (en) 2008-08-29
ZA200510132B (en) 2006-08-30
JP4757197B2 (ja) 2011-08-24
NO20056089L (no) 2006-02-09
WO2004103381A1 (en) 2004-12-02
ES2294507T3 (es) 2008-04-01
HK1084023A1 (en) 2006-07-21
CA2526201A1 (en) 2004-12-02
RU2005138517A (ru) 2006-08-27
AU2004241748A1 (en) 2004-12-02
AU2004241748B2 (en) 2010-05-13
US20060205690A1 (en) 2006-09-14
PL1631298T3 (pl) 2008-04-30
IL171981A (en) 2010-04-15
ATE373480T1 (de) 2007-10-15
DE602004009068D1 (de) 2007-10-31
CN100377717C (zh) 2008-04-02
EP1631298A1 (de) 2006-03-08
ITMI20031023A1 (it) 2004-11-22
JP2006528670A (ja) 2006-12-21
RU2353371C2 (ru) 2009-04-27
CN1791416A (zh) 2006-06-21

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